As previously stated, there are many tools in existence to identify who should have genetic testing to establish a diagnosis of Lynch Syndrome. Unfortunately, many providers are unaware of these tools and if they do screen patients for hereditary cancer syndromes, they do so based on the classic findings of early age of diagnosis of cancers or multiple Lynch associated cancers in family members over use of validated screening tools (16, 17).

Use of family-history based criteria are the earliest standardized methods proposed for who should be tested for Lynch syndrome. Use of the Amsterdam II Criteria is one of these methods, and recommends testing an individual for Lynch syndrome when they meet all of the following criteria: 1) having 3 relatives with any Lynch-associated cancer with 1 being the first degree relative of the other 2, 2) there are 2 successive generations are affected, and 3) 1 is diagnosed before the age of 50 (18). The sensitivity and specificity of the Amsterdam II Criteria have since been determined to be 25-72% and 78-98%, respectively (19, 20). The low sensitivity is certainly a weakness of this screening method, though a benefit is that it does not require an individual to already be diagnosed with a cancer prior to screening, and considers Lynch-associated cancers other than colorectal cancer, which is important for those approaching screening from a women’s health perspective. The Amsterdam II Criteria were followed by the Bethesda Criteria and Revised Bethesda Criteria, a set of guidelines based on personal and family history for when patients with colorectal cancer should have their tumors tested for microsatellite instability (MSI), a pathologic hallmark of Lynch-associated cancers (21). The sensitivity and specificity of the Revised Bethesda Criteria were determined to be 50-94% and 25-75% respectively (19, 20). In addition to a lower specificity, from a gynecologic perspective, this screening method is limited by the fact that it requires a colorectal cancer diagnosis and does not take into account endometrial and ovarian malignancies, though the American College of Obstetricians and Gynecologists (ACOG) has made modifications to extrapolate the criteria to gynecologic cancers (22). Furthermore, it is not able to identify individuals with Lynch syndrome prior to a cancer diagnosis. The Society of Gynecologic Oncologists (SGO) also developed guidelines in 2007 that placed individuals within two risk categories (20-25% risk and 5-10% risk) of having Lynch syndrome that were based on the Amsterdam criteria and Bethesda criteria (23). However, follow-up studies show a relatively low sensitivity of SGO criteria consistent with studies of Amsterdam and Bethesda criteria (24, 25).

Clinical prediction models were developed to improve the detection of individuals with Lynch syndrome compared to methods based primarily on family history such as the Amsterdam II Criteria and Revised Bethesda Criteria. Their strength is that they screen for Lynch syndrome prior to a person being diagnosed with cancer. Several models have been created, such as MMRpredict, MMRpro, and PREMM5 (26–28). Each model is somewhat different based on variables they take into account, including characteristics such as age, sex, age at diagnosis of cancer, family history of cancer with family ages of diagnosis, and testing results, if available. However, each is similar in that they are designed to quantify the likelihood a person has a PV in an MMR gene, guiding counseling for the decision to pursue genetic testing. The advantage of these models is that they are simple, validated tools for providers to employ in cancer unaffected individuals that may improve upon the screening test characteristics of the Amsterdam II Criteria and the Revised Bethesda Criteria, though comparative studies are few and conflicting (26, 29, 30). However, it is important to note that not all models quantify risk for PVs in all Lynch-associated genes. Importantly, it should be noted that MMRpredict is validated for patients with colorectal cancer rather than endometrial or ovarian cancers, while MMRpro considers endometrial cancer and PREMM5 considers both endometrial cancer and other Lynch-associated cancers including ovarian cancer (26–28). Gynecologic providers must be aware of this when selecting a clinical prediction model if this is the screening method they choose to utilize.

The current standard of care in screening for Lynch syndrome in those who are affected by cancer is tumor-based testing of patients for loss of expression of MMR proteins with immunohistochemical staining (IHC) (31). IHC staining detects the presence of MMR proteins, and staining is lost when there is a loss or defect in an MMR gene as is seen in Lynch syndrome. This is generally an indication for germline MMR gene testing for diagnosis of Lynch syndrome, though there are additional steps such as MLH1 hypermethylation testing depending on the pattern of loss of expression visualized to determine whether the loss of expression is sporadic or a result of a germline PV. An adjunct or lesser alternative to IHC staining is tumor-based MSI testing (11). MSI testing is traditionally performed using polymerase chain reaction (PCR) to identify expansion or contraction of repetitive DNA sequences within the tumor that are prone to error, and is recommended when IHC results are equivocal. Tumors that show a certain degree of this expansion or contraction are determined to be MSI-high (MSI-H). Most Lynch tumors are MSI-H, but only about 16% of MSI-H tumors are associated with Lynch syndrome (32). MSI-H tumors are, however, an indication for Lynch genetic testing if identified, regardless of type of malignancy. Tumor testing as a screening method offers the greatest sensitivity and specificity of the methods described, but unfortunately requires a cancer diagnosis for screening to be completed, thus limits primary prevention of cancer in those with Lynch syndrome, though it does offer options for prevention of metachronous malignancies.

When it comes to tumor testing as a method of screening for Lynch syndrome, a key question is knowing which tumors to test. The Revised Bethesda Criteria offer one solution to this question, though may miss 12-30% of Lynch-associated tumors and would need modification and ideally validation for patients with endometrial or ovarian cancer (8). Universal screening of tumors allows the greatest detection of Lynch syndrome, but whether or not it is truly cost-effective remains in question. Studies in colorectal cancer populations support universal colorectal tumor testing as reasonably cost-effective (33). A study in the United Kingdom also found universal IHC staining of endometrial tumors to be cost-effective (34). However, a cost-effectiveness study on a variety of testing criteria in women with endometrial cancer in the United States calculated an incremental cost-effectiveness ratio (ICER) of $648,494 per life year gained for universal endometrial cancer tumor testing, which was significantly greater than $9,126 per year of life gained for the recommended strategy of testing the tumors of all women endometrial cancer with at least 1 first degree relative with Lynch-associated cancer diagnosed at any age (35). Regardless of the cost, because of enhanced detection of Lynch syndrome and prognostic implications of certain molecular subtypes of endometrial carcinomas, universal tumor testing is now recommended by several professional societies, including the National Comprehensive Cancer Network (NCCN), Society of Gynecologic Oncology (SGO), ACOG, and European Society for Medical Oncology (ESMO) (22, 36–38) Whether or not universal endometrial tumor testing as a screening method for Lynch syndrome is performed and the extent of testing may be institution-dependent at this time due to cost and pathology expertise. This poses an issue for equitable care and hopefully further study and technology advances can standardize screening. As for ovarian cancer, NCCN guidelines recommend germline and tumor testing for all patients diagnosed to not only evaluate for Lynch syndrome, but also to evaluate for BRCA mutations and other molecular features that may influence treatment decisions (39). Current guidance from SGO on identifying patients with an increased likelihood of Lynch syndrome takes into account family history as well as molecular based tumor screening techniques ( Table 2 ) (37).

Despite gradual improvements in the detection of individuals at risk for Lynch syndrome, there continues to be a significant number who remain undiagnosed, and development of novel screening strategies or technology to improve access to screening should be a priority. One suggested solution includes use of remote genetic counseling to better identify high-risk individuals who may not have access to in-person genetic counseling, which has been shown to produce similar levels of patient knowledge and satisfaction and reduces costs, but may result in lower counseling and testing completion rates compared to in-person counseling (40, 41). Additionally, genetic counseling itself requires a provider referral, which adds a step in the screening process and therefore adds a barrier. Genetic counseling by providers other than genetic counselors has been explored to remove this barrier, though this is dependent on provider acceptability of and comfortability with performing their own genetic counseling. One recent study evaluated the feasibility of gynecologist led Lynch syndrome counseling and testing, rather than sending a patient to a genetic counselor prior to testing, and results were favorable in terms of acceptability by women being tested and uptake of testing upon counseling (42). Another proposed solution to the genetic counselor barrier suggests use of health information technology in the form of chatbots with which individuals can directly interact (43). These chatbots use an individual’s input and standardized risk assessment tools to produce a risk estimate for hereditary cancer syndromes. They can then facilitate genetic testing, counsel regarding results, and assist with cascade testing virtually. One study evaluating use of a chatbot revealed patient knowledge and genetic testing completion rates similar to those achieved through genetic counseling, but low rates of individuals initiating interaction with the chatbot and low provider interest or comfort in results follow-up (44). Studies evaluating patient and provider acceptability of chatbots and process implementation are ongoing. Population-based genetic testing for germline PVs has also been proposed given improvements in DNA sequencing and lower costs (45). Indeed, this method identifies many individuals with hereditary cancer syndromes who would not otherwise meet high-risk criteria, but is not cost-effective at this time, and the stress of finding variants of unknown significance (VUS) may adversely affect some individuals.

Once a person has been screened as high-risk for Lynch syndrome using one of the methods above, the definitive diagnosis can be established through germline testing. This can be done through several methods: multigene panel testing, targeted MMR gene testing, or single gene testing. The National Comprehensive Cancer Network (NCCN) recommends single gene testing if there is a known PV within a person’s family and if they are clinically low-risk for other PVs (46). Multigene panel testing, in which several cancer predisposition PVs are sequenced, is recommended for those at high-risk for Lynch syndrome but without a known PV in the family due to the possibility of another hereditary cancer syndrome placing the individual in the high-risk category. MMR PV testing may be best for those with a specific IHC pattern after tumor testing. Multiple professional societies, including ACOG and NCCN, agree that it is best practice to involve cancer genetics experts, such as genetic counselors, whenever genetic testing may be performed. However, given a national shortage of these skilled professionals, this may not be a resource for all, and presents an area for improved access for equitable high-risk care (22, 46).

Interpretation of genetic testing results is key to counseling( Table 3 ) (47). VUS are changes or alterations in the genetic code for which the downstream protein function is unknown and are sometimes the most clinically challenging result to contextualize for patients. As there is increased utilization of multigene panels in broader populations, more VUSs will be identified (48). Approximately 80-90% of VUSs will subsequently be reclassified as benign polymorphisms and should be treated as clinically negative (49). In addition, an increasing number of individuals present to care having completed direct to consumer testing (DTC), where these individuals interact directly with testing companies. There is a wide range of DTC companies with different testing methodology and interpretation of results. Currently, any PV identified on DTC should be verified through a clinical lab (47). Lastly, there are families that meet Amsterdam criteria and a germline PV is not identified in the family. These individuals may be followed as having clinical Lynch syndrome, however, this should be done in consultation with a high-risk expert.

Once an individual is diagnosed with Lynch syndrome, they should be counseled regarding both their personal risk of cancer and also their family’s potential risk. This should include a conversation regarding cascade testing, which involves genetic testing of a known carrier’s relatives to determine whether these family members are affected, and thus also at increased risk. Cascade testing is recommended to begin with first-degree relatives, as these individuals have a 50% chance of having the same Lynch syndrome PV, and if positive, expand cascade testing to their first-degree relatives (50). Generally, these individuals need only be tested for the known PV that has been identified in their family rather than testing for all PVs associated with Lynch syndrome. Cascade testing enhances the ability to identify more carriers with Lynch syndrome that otherwise might not be screened, and improves the cost-effectiveness of universal tumor testing (51).

Another consideration to offer individuals interested in reproduction upon diagnosis of Lynch syndrome is referral to a reproductive endocrinology and infertility (REI) specialist to discuss preimplantation genetic testing (PGT). This diagnostic test is used in conjunction with in vitro fertilization (IVF), and involves testing an embryo in the lab for a specific PV to reduce the risk of passing this PV on to future children. For Lynch syndrome, this would mean testing the embryos of a Lynch syndrome carrier and their partner for the specific MMR PV the carrier is known to have. Identifying which embryos carry this PV allows the REI specialist to inform the parents undergoing IVF and selectively transfer embryos that are not carriers, thus preventing a future child from being affected by Lynch syndrome. It is important to address the timing of IVF if the Lynch syndrome carrier is female, as it may be affected by the recommended timing of risk-reducing hysterectomy to prevent endometrial cancer or risk-reducing oophorectomy to prevent ovarian cancer, as is discussed in the next section (52).

Multiple approaches to screening for endometrial cancer in asymptomatic women diagnosed with Lynch syndrome have been proposed, including endometrial biopsy and transvaginal ultrasound (TVUS). Importantly, none of these methods have been shown to reduce the morbidity and mortality of women with Lynch syndrome (53–56). This is likely due to the fact that the majority of endometrial cancers are already diagnosed with early stage disease and any screening intervention will not improve dramatically on the early stage of diagnosis overall for endometrial cancer. Despite a lack of proven efficacy, and given the low risk of screening tests and high risk of endometrial cancer in this population, multiple professional societies including ACOG and NCCN agree that endometrial biopsy every 1-2 years starting between the ages of 30 and 35 can be considered in women diagnosed with Lynch syndrome (22, 46). Many experts go on to recommend starting screening with endometrial biopsy 10 years before the earliest Lynch-associated cancer diagnosis in the family and to continue endometrial biopsies until the time of hysterectomy. Endometrial biopsy is the test of choice due to its excellent sensitivity of 91-99.6% and specificity of 98% for endometrial cancer and hyperplasia, as well as evidence that it enhances detection of endometrial cancer and hyperplasia compared to TVUS alone (54, 57). It is, however, an invasive and uncomfortable test, which may impact acceptability to patients. There is prospective evidence from patient reported outcomes that performing endometrial biopsy at the time of colonoscopy decreased pain associated with the biopsy (58). While this was shown to be feasible in the setting of a study, whether this is feasible in practice depends on many factors, most notably where colonoscopies are performed within individual practices.

TVUS is less invasive than endometrial biopsy, however, it offers lower detection rates and it is not recommended in premenopausal females since endometrial thickness varies greatly throughout a menstrual cycle (46, 54). A few studies have investigated the combination of endometrial biopsy and TVUS, which shows promise in increasing detection, but again, does not offer definitive morbidity or mortality benefit at this time (55, 59).

Additional methods of screening for endometrial cancer have been proposed and show potential, but currently lack sufficient evidence supporting efficacy required of a suitable screening test in a clinical setting. The use of pap smears and tampon-based intravaginal sampling to detect cancerous endometrial cells, shed tumor DNA, or biomarkers are a few of these methods (60–63). One such study evaluating 18 genes in fluid collected via pap smear for endometrial and ovarian cancer patients in comparison to cancer-free controls found a specificity of 99%, though it was limited by modest sensitivity (78% for endometrial cancer, 33% for ovarian cancer) (63). Analysis of urinary samples for potential endometrial cancer biomarkers, such as estrogen metabolites, has also been proposed by several studies and is interesting as a simple, non-invasive form of screening, but to date none of the biomarkers suggested have been validated (64–66). Each of these will be ideas to watch over the next several years.

For women diagnosed with Lynch syndrome who present with symptoms, including but not limited to abnormal bleeding, pelvic mass or pain, abnormal discharge, or weight loss, women’s health providers should have high suspicion for endometrial cancer and investigation in the form of endometrial biopsy and/or transvaginal ultrasound should be performed.

Risk reduction of endometrial cancer is another aspect of management of which providers and women with Lynch syndrome need to be aware ( Table 4 ). The most invasive method, and that with the greatest evidence for prevention of endometrial cancer in this population, is risk-reducing hysterectomy and bilateral salpingectomy with or without oophorectomy. The largest study comparing outcomes between women with Lynch syndrome who underwent risk-reducing surgery and those who did not found that 0% of patients who underwent hysterectomy were diagnosed with endometrial cancer after 13 years of follow-up compared to 33% of those who did not have a hysterectomy (14). The timing of this intervention is controversial given lack of strong evidence dictating a specific age, though desire for fertility, age at cancer diagnosis in Lynch-affected family members, diagnosis of other cancers, and even specific PV should all be considered (46). Given a 4-fold increase in endometrial cancer risk from the age of 40 to the age of 50, many professional societies, including ACOG and SGO, recommend risk-reducing hysterectomy by the age of 40-45 (4, 22). Surgery before age 40 can also be considered if a woman has completed child-bearing, and indeed, the American Society for Clinical Oncology (ASCO) recommends this (67). A cost-effectiveness analysis comparing multiple ages for surgery found that annual screening until hysterectomy at age 40 was most effective at preventing endometrial cancer, but risk-reducing surgery at age 40 without screening was the most cost-effective given the substantial cost of screening and hormone replacement therapy for surgical menopause when surgery was performed at age 30 (68). Despite these results, expert consensus is to continue screening for endometrial cancer until hysterectomy is performed, at which point it can be discontinued. For those desiring fertility, referral to a reproductive endocrinologist should be considered prior to surgery, especially if they are approaching advanced maternal age. If colorectal cancer is diagnosed prior to risk-reducing gynecologic surgery, a joint procedure with colorectal surgery can be planned and this can also dictate timing of surgery. Regardless of timing, colonoscopy and endometrial biopsy should be up to date prior to risk-reducing surgery to rule out occult malignancies and be sure the appropriate procedure is being planned.

Lifestyle and medical chemoprevention options should also be discussed with individuals with Lynch syndrome. In accordance with general population recommendations, those with Lynch syndrome should be counselled to maintain or attain a normal body weight given the well-defined association of obesity with the development of endometrial cancer. They should also be counselled to engage in 30 minutes of exercise daily or 150-300 minutes of moderate intensity exercise weekly exercise per American Cancer Society (ACS) guidelines (69).

As for medical chemoprevention, there is evidence that daily aspirin may be associated with a reduction in all Lynch-associated cancer diagnoses in those with Lynch syndrome (70). The CAPP2 trial is a multinational randomized controlled trial examining differences in colorectal and all Lynch cancer diagnoses in those with Lynch syndrome based on use of daily aspirin. Individuals were randomized to receive either placebo or 600mg of aspirin daily. After an average of 10 years of follow-up, colorectal cancer and all Lynch cancer diagnoses were found to be significantly lower in those taking daily aspirin, though there was no difference noted for all non-colorectal Lynch cancer diagnoses. While the benefit for endometrial or ovarian cancers is unclear, there is benefit for colorectal cancer and thus women with Lynch syndrome can be offered daily aspirin for their comprehensive care if there are no contraindications.

Hormonal therapies, including combined oral contraceptive pills (OCPS), oral progestins, or progesterone containing intrauterine devices (IUDs), are an alternative form of risk-reduction for those with Lynch syndrome prior to completion of childbearing and risk-reducing hysterectomy. Data for endometrial cancer prevention with hormonal therapies in the Lynch population specifically are limited and the majority of evidence is extrapolated from studies in the general population (71–73). Population based evidence shows that OCP use for 5 years decreases endometrial cancer risk by 50-70%, with increased protection with longer duration of treatment (74). Similarly, retrospective evaluation showed a 61% risk reduction in endometrial cancer among women with Lynch syndrome who used hormonal contraception in the form of combined or progestin only pill, the implant, or the injection for at least one year (75). A small randomized controlled trial examined the effect of Depo-Provera versus progestin-only oral contraceptives in a population of women with Lynch syndrome, which revealed a decrease in endometrial proliferation in both groups, but was not able to compare endometrial cancer rates between the groups (76). Progesterone containing IUDs, which are now utilized to treat endometrial intraepithelial neoplasia and low grade endometrial cancers, are also associated with an approximate 50% decreased risk of endometrial cancer in the general population and this decreased risk persists for 5 year following discontinuation (77–79).

As with endometrial cancer, multiple screening methods for the early detection of ovarian cancer have been proposed for asymptomatic women with Lynch syndrome, though no evidence exists supporting an improvement in morbidity or mortality for any method (55, 56). Annual transvaginal ultrasound is one method that has been studied, but has relatively poor sensitivity and specificity for ovarian cancer and thus can be considered, but is not formally recommended by major professional gynecologic or oncology professional organizations such as ACOG, SGO, or NCCN (22, 46, 80). The same is true for the measurement of CA 125. Importantly, there are no studies on these screening methods in the Lynch syndrome population specifically, they are only available from the general population or among those with BRCA mutations (81–84). This is problematic because Lynch-associated ovarian cancer is different from BRCA-associated ovarian cancer. Lynch associated ovarian cancers tend to be mostly endometrioid and have a more favorable prognosis than the aggressive serous ovarian cancers associated with BRCA mutations (85). They also derive from different molecular pathways. Thus, combining these two very different types of ovarian cancers under one umbrella based on evidence availability, or lack thereof, should be done with great caution. Certainly, more studies in a Lynch population are needed.

Any female with Lynch syndrome presenting with bloating, a palpable mass, abdominal pain, weight gain or loss, early satiety, or other concerning symptoms should undergo imaging to determine if ovarian cancer is present.

Risk-reducing surgery for the prevention of ovarian cancer in those with Lynch syndrome is currently one of the most difficult clinical questions to consider in high-risk care for the individual as differential lifetime risks of ovarian cancer for specific Lynch variants have been better outlined in recent years ( Table 4 ). Most data evaluating risk reduction for ovarian cancer include bilateral salpingo-oophorectomy (BSO) with tubes and ovaries removed at the same time and includes data for all variants in aggregate, rather than for individual variants. This is critical to understand for counselling, especially those with PV in MSH6 and PMS2, where there is no strong recommendation for oophorectomy based on current available evidence. It should be noted throughout the discussion that regardless of the recommendation for bilateral oophorectomy, bilateral salpingectomy is recommended at the time of risk reducing hysterectomy (86, 87).

NCCN currently recommends for MLH1 and MSH2/EPCAM carriers that the decision to have a BSO as a risk-reducing option should be individualized and timing should be based on completion of childbearing, menopausal status, medical comorbidities, family history, and specific variant. Differently, NCCN states that for MSH6 carriers, insufficient evidence exists to make a specific recommendation for BSO and that the decision should be individualized. They are even more detailed in their recommendation for PMS2 carriers and state that PMS2 carriers appear to be at no greater risk of ovarian cancer and that individuals may reasonably elect not to have an oophorectomy (12).

In a study evaluating BSO compared to no BSO for the prevention of ovarian cancer in 223 individuals with Lynch syndrome, no one who underwent BSO was diagnosed with ovarian cancer, while 5% who did not undergo BSO were ultimately diagnosed with ovarian cancer, supporting BSO as a reasonable method of risk reduction (14). Ovarian cancer risk in those with Lynch syndrome triples from the age of 40 to the age of 50 depending on the PV, therefore timing recommendations of surgery before age 45 are the similar to endometrial cancer (4). Hormone replacement therapy (HRT) is generally considered safe for the treatment of surgical menopause after BSO in premenopausal women, though has not been directly studied in a Lynch population. Given that hysterectomy is also recommended for risk reduction, women benefit from needing estrogen replacement therapy (ERT) alone. Expert opinion is for consideration of HRT for women with Lynch Syndrome who undergo premenopausal BSO (46). Interestingly, there is evidence of a protective effect of HRT against the development of colorectal cancer in the general population, and this may be helpful for women with Lynch syndrome who have an increased risk of colorectal cancer, though further study in this specific population would be needed (88).

For the individual, discussion of the risks and benefits of oophorectomy is paramount in the Lynch population and should include a gynecologic provider experienced in high-risk care. For most, the decision is whether to proceed with oophorectomy at the time of hysterectomy and bilateral salpingectomy. Several factors should be taken into account on top of completion of childbearing, most notably age, family history of ovarian cancer and age of diagnosis, as well as other medical and surgical co-morbidities. Regardless of the individual variant, if an individual is ready to proceed with risk reducing hysterectomy at 35, a well-documented and thorough discussion of oophorectomy is necessary, most notably including the risk of early surgical menopause, including increased risk of osteoporosis, cardiovascular disease, and effects on cognitive as well as sexual function. In addition, there is mounting evidence that the majority of high grade serous ovarian cancers originate in the distal fallopian tube. Opportunistic salpingectomy is associated with a 42-64% reduction in the risk of ovarian cancer in epidemiologic studies (89–91). There are ongoing studies in the BRCA population for this, but the degree to which salpingectomy decreases the risk of Lynch associated ovarian cancers specifically is largely unknown, where the incidence of non-serous ovarian cancers are higher than in the BRCA population (92). Delayed oophorectomy is an option for those who wish to defer menopause with appropriate counselling, though this would require a second surgery if hysterectomy is done earlier and surgery thus may be more complicated (93).

Ovarian cancer chemoprevention with combined estrogen and progestin oral contraceptive pills (COCPs) is an option for women with Lynch syndrome, though again, there are no studies in the Lynch syndrome population. Studies in the general or BRCA populations do suggest a benefit in ovarian cancer prevention with the use of COCPs, but again, Lynch-associated ovarian cancer is fundamentally different than BRCA-associated ovarian cancer, thus it is not clear whether a true benefit exists in the Lynch syndrome population (46, 94–97). Premenopausal females with Lynch syndrome who have not completed childbearing and thus have not yet undergone risk-reducing hysterectomy and BSO can have a risk/benefit discussion with their provider to determine if chemoprevention with COCPs is the right choice for them.

An exciting intervention that may be on the horizon for cancer prevention in carriers of Lynch syndrome is that of cancer vaccines. These investigational vaccines are developed against neoantigens produced by frameshift mutations in those with MSI-H tumors and Lynch syndrome (98). There are currently multiple registered clinical trials investigating the development of vaccines to prevent cancer in those with Lynch syndrome specifically (99).